RESUMEN
Colorectal cancer (CRC) is a complex disease with still unsatisfactory prognosis even in western societies, although substantial progress has been made in pre-screening programs, surgical techniques and targeted therapy options. Mediator of motility-1 (Memo-1) was previously recognized as an important effector of cell migration downstream of receptor tyrosine kinase signaling in breast cancer. This study identified Memo-1 as frequently overexpressed in CRC and established a close link between extracellular HER2 activation, AhR/ARNT transcriptional activity and Memo-1 expression. Dissection of the hMemo-1 gene promoter using reporter assays and chromatin IP techniques revealed recruitment of Aryl hydrocarbon receptor (AhR)/Aryl hydrocarbon receptor nuclear-translocator (ARNT) complex, which positively influenced Memo-1 expression in cancer cells. We found that Memo-1 depletion negatively influenced the cellular actin network and that its expression is required for HER2-mediated cell migration and invasion. Moreover, analyses of Memo-1 expression in primary CRC revealed correlation with clinical parameters that point to Memo-1 as a new prognostic factor of aggressive disease in CRC patients. Altogether, these observations demonstrate that Memo-1 is an important downstream regulator of HER2-driven CRC cell migration and invasion through connecting extracellular signals from membrane to the cytoskeletal actin network.
Asunto(s)
Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , Proteínas de Hierro no Heme/genética , Proteínas/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Línea Celular Tumoral , Movimiento Celular , Progresión de la Enfermedad , Humanos , Péptidos y Proteínas de Señalización Intracelular , Invasividad Neoplásica , Regiones Promotoras Genéticas/genética , Transducción de SeñalRESUMEN
INTRODUCTION: Expression of cancer testis antigens (CTAs) has been associated with prognosis in gastrointestinal stromal tumors (GIST) and other malignancies. CTAs are currently being investigated for cancer immunotherapy. MATERIALS AND METHODS: We analyzed two CTAs, CT10/MAGE-C2 and GAGE, in 51 GIST by immunohistochemistry and correlated it with established histopathological criteria for malignancy. RESULTS: GAGE expression was found in 6/51 (12%) patients, whereas 5/51 (10%) patients expressed CT10/MAGE-C2. 7/51(14%) patients expressed at least one of both CTAs, in 4/51 (8%) patients both CTAs were positive. High-grade GIST are more likely to express GAGE (p = 0.002) and CT10/MAGE-C2 (p = 0.007) compared to less aggressive tumors. All patients with GAGE or CT10/MAGE-C2 expression had moderate- or high-risk of recurrence according to the established risk criteria. The presence of GAGE correlates with mitotic rate (p = 0.001) and tumor size (p = 0.02), but not with tumor location (p = 0.60). CT10/MAGE-C2 also significantly correlates with mitotic rate (p = 0.004) and tumor size (p = 0.002), whereas no correlation could be found with tumor location (p = 0.36). DISCUSSION: CT10/MAGE-C2 and GAGE should be explored together with other previously described CTAs as targets for immunotherapy of GIST in cases, which are refractory to conventional therapy.
